tbuckley/cabot-search huggingface dataset:
EXTH-93. THE IRAK-4 INHIBITOR EMAVUSERTIB (CA-4948) FOR THE TREATMENT OF PRIMARY CNS LYMPHOMA
Authors: Christina von Roemeling, Bently Doonan, Kelena Klippel, Lan Hoang-Minh, Elizabeth Ogando-Rivas, Elizabeth Martinez, Paul Castillo, Madiha Iqbal, Han Tun, Reinhard von Roemeling, Duane Mitchell
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND PCNSL is an aggressive brain tumor accounting for 3% of all CNS malignancies and is associated with poor prognosis. Standard of care treatment includes induction with high-dose methotrexate based chemoimmunotherapy followed by consolidation with autologous stem cell transplant or whole brain radiation. However, more than half of PCNSL patients cannot tolerate this intensive therapeutic intervention. Novel treatments are urgently needed. Toll-like receptor signaling pathway via MyD88/IRAK-4 signalosome is constitutively active in PCNSL secondary to MYD88 L265P mutation and represents an excellent therapeutic target. Emavusertib (CA-4948) is an oral first-in-class small molecule inhibitor of IRAK-4 that demonstrates clinical activity in patients with systemic Non-Hodgkin’s Lymphoma, however it has not been evaluated in the CNS space. HYPOTHESIS: Emavusertib has anti-tumor activity against preclinical PCNSL. METHODS Using multiparameter immunohistochemistry (IHC) and proteomics analysis, IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient PCNSL tissues as compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for emavusertib drug concentration following single oral high dose in a murine model. Survival responses in preclinical PCNSL models were measured in response emavusertib treatment, along with in vivo tumor proliferation and downstream biomarker expression by multi-parameter IHC. RESULTS Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient PCNSL. We show that emavusertib can achieve therapeutically relevant concentrations in the brain and CSF. Emavusertib impairs tumor cell proliferation in vitro and in vivo, and shows dose-dependent single-agent activity in preclinical PCNSL models. We confirm decreased ERK1/2, MAPK and NF-κB activation, indicative of downstream IRAK-4 inhibition. CONCLUSIONS Our data supports that emavusertib demonstrates anti-tumor activity in the CNS space, warranting further preclinical and clinical evaluation of this agent for the treatment of PCNSL.
NCMP-07. CASE SERIES OF REGULARLY SCHEDULED MANNITOL INFUSIONS SHOWING WITH PROLONGED CLINICAL BENEFIT FOR MANAGEMENT OF CEREBRAL EDEMA IN GLIOMAS
Authors: Jared Chow, Jose Carrillo, Santosh Kesari, Akanksha Sharma, Minh Nguyen, Judy Truong, Naveed Wagle
Journal: Neuro-Oncology (2022)

Abstract Gliomas account for the vast majority of malignant primary tumors arising in the central nervous system. Elevated intracranial pressure (ICP) may be a potentially devastating complication of brain tumors and hydrocephalus. Brain tumors may occupy significant space causing displacement and compression of delicate structures within a finite intracranial compartment. The compliance relationship is nonlinear and decreases as the combined volume of the intracranial contents increases. When these compensatory mechanisms have been exhausted, significant increases in pressure develop with relatively small increases in volume. The diagnosis of elevated ICP is generally based on clinical findings and corroborated by imaging studies and the patient's medical history. The best therapy for intracranial hypertension (ICH) is the resolution of the proximate cause of elevated ICP such as the evacuation of a blood clot, resection of a tumor, or cerebrospinal fluid (CSF) diversion in the setting of hydrocephalus. If these modalities have been exhausted or unavailable, osmotic diuretics such as mannitol can be utilized. This medication reduces brain volume by drawing free water out of the tissue and into the circulation, where it is excreted by the kidneys, thus dehydrating brain parenchyma. The common belief is that effects are usually present within minutes, peak at approximately one hour, and last 4 to 24 hours. We report a series of 33 patients treated for a minimum of 1 month of regularly scheduled maintenance infusions of Mannitol 1g/kg every two weeks, 64% showed improved clinical outcomes or stabilization of edema clinical symptoms. Patients expressed improvements in headaches, dizziness, and cognitive ability. This supports the bi-weekly maintenance use of Mannitol in glioma patients with symptomatic cerebral edema. A controlled trial should be supported. This series also suggest a mechanism of action with a more durable response than osmotic diuresis.
QLTI-01. THE EFFECT OF COMPLETE RESECTION OF CONTRAST-ENHANCING TUMOR ON SURVIVAL IN PATIENTS WITH GLIOBLASTOMA OVER A 16-YEAR PERIOD IN A GEOGRAPHICALLY DEFINED POPULATION
Authors: Eduardo Erasmo Mendoza Mireles, Einar Osland Vik-Mo, Erlend Skaga, Eirik Helseth, Pål Andre Rønning, Andres Server, Petter Brandal
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The median survival for patients with glioblastoma is less than one year, and survival beyond five years is rare. Radiotherapy combined with chemotherapy has improved survival since its introduction in 2005. No new treatment modalities have been widely adopted after this, but treatment development has focused on achieving maximal resection and the introduction of coordinated clinical care pathways. We hypothesize that these changes in approach have resulted in an improved survival in surgically treated patients. METHODS Retrospective analysis of a prospectively collected database in the adult population (2.4 million habitants) of South-Eastern Norway. Patients were divided in three periods; radiotherapy- (2003-2005), temozolomide- (2006-2012), and resection focused-period (2013-2019). Patients were also stratified according to age and grade of resection. Relative survival, Cox hazard-ratio, 3- and 5- year survival were calculated. RESULTS We identified 1663 surgically treated glioblastoma patients eligible for the study. The median overall survival was 11.4 months. Complete resection of contrast-enhanced tumor (CRCET) was achieved in 387 (23.2%) patients. The frequency of CRCET increased during the observation time (32 - 116 - 239), but there was no increase in reoperation rates (13%). Significant improvement between the last period and the first two periods was observed (12.3 vs. 10.5 months, p &amp;lt; 0.006), with a significant increase in 3- and 5- year survival probability between the first two groups (p = 0.01). No difference was found in median survival in CRCET among periods. Patients with CRCET demonstrated significantly longer median survival than patients with non-CRCET (16.1 vs. 10.8 months; p &amp;lt; 0.001). Incidence in the elder group increased from 2.6 to 13.2 per 100,000 habitants, and median survival doubled when CRT was achieved. CONCLUSIONS There is an increase in median survival, 3- and 5- year survival probability when comparing time-periods. We suggest this survival benefit is related to improved CRCET rates.
RADT-04. SINGLE SESSION GAMMA KNIFE RADIOSURGERY TO TREAT PATIENTS WITH 20 OR MORE BRAIN METASTASES
Authors: Zhishuo Wei, Diego Luy, Sila Yavan, Shalini Jose, Stephen Worrell, J Raouf Belkhir, Hansen Deng, Ajay Niranjan, L Dade Lunsford
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Stereotactic Radiosurgery (SRS) has become a primary management option for brain metastases (BMs). This present study aims to review outcomes in patients with ≥ 20 BMs treated in a single session SRS and to identify predictors of local tumor control (LTC) and overall survival (OS). METHODS We identified 75 patients including 26 non-small cell lung cancer (NSCLC), 21 small cell lung cancer (SCLC), 14 breast cancer (BC), and 14 melanoma patients who underwent SRS for ≥ 20 BMs between 2014 and 2020. The median number of tumors was 24 (range 20 – 52), and the median cumulative tumor volume was 3.70 cc (0.13 – 62.49 cc). The median margin dose was 16 Gy (14 – 20 Gy). Median skull integral dose was 5492 mJ (range 1372 – 11243 mJ). The median treatment time for each session was 160 min. Outcome variables were assessed using univariate and multivariate analyses with p &amp;lt; 0.05. RESULTS Median OS after SRS was 5.8 months (range 0.1 – 73.2 months). Primary cancer type and concurrent immunotherapy were significant predictive factors for patient OS after SRS (p = 0.01, 0.05, and 0.02, respectively). LTC rate at 6 and 12 months after SRS was 95.7% and 83.7%, respectively. Thirty (40.0%) patients underwent additional SRS and 3 patients (4%) received post-SRS WBRT due to distant tumor recurrence. The median time to distant recurrence was 5 months (range 2-28 months). SRS-induced adverse radiation effects (ARE) events were observed in 3 patients (4.0%; 1 NSCLC, 1 SCLC, and 1 melanoma). CONCLUSIONS Our results suggest that patients with ≥ 20 BMs can be safely treated with SRS with an excellent LTC rate and a low risk of ARE. Newly developed BMs can be treated with repeat SRS. This single-session SRS allows patients to proceed with systemic cancer care without interruption.
PATH-19. CLINICAL AND MOLECULAR FEATURES OF GLIOBLASTOMA, IDH-WILDTYPE ARISING IN THE SETTING OF LI FRAUMENI SYNDROME
Authors: Yuji Kibe, Fumiharu Ohka, Kazuya Motomura, Kosuke Aoki, Sachi Maeda, Junya Yamaguchi, Tomohide Nishikawa, Kosuke Mizutani, Hiroki Shimizu, Taku Hiramatsu, Kazuaki Suzuki, Ryuta Saito
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Li Fraumeni Syndrome (LFS) is a rare autosomal dominant tumor predisposition syndrome caused by germline alterations of the TP53. Brain tumors are included in LFS core cancers. Choroid plexus carcinomas and medulloblastomas tend to occur in pediatric LFS patients, while gliomas tend to occur in adult LFS patients. There are few previous reports about gliomas arising in the setting of LFS. Here, we report clinical and molecular features of three cases of glioblastoma, IDH-wildtype arising in the setting of LFS. RESULTS Mean age at diagnosis was 40 years (range: 32-45). Two patients were male. Two patients had medical history of multiple tumors and family history of brain tumors. Magnetic resonance imaging of each patients revealed a left cerebellar peduncle lesion with faint contrast-enhancement, a right parietal lobe lesion with nodular contrast-enhancement and two lesions in the pons (no enhancement) and right parietal lobe (ring enhancement), respectively. All patients underwent chemotherapy including temozolomide and/or bevacizumab combined with radiation therapy (60Gy) after surgery. Mean progression free survival was 10.4 months (range: 5.1-17.0). All patients were admitted to palliative care mean 17.3 months (range: 14.4-21.4) after diagnosis. All patients harbored heterozygous germline mutations of TP53. Whole exome sequencing and copy number analysis of tumor tissues revealed TP53 mutation and PDGFRA amplification in all patients. However, EGFR amplification, the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-) and mutations of IDH, H3F3A, BRAF and TERT promoter were not detected in all tissues. CONCLUSION We experienced three cases of glioblastoma, IDH-wildtype arising in the setting of LFS. Although tumor locations and radiographic features were varied, all clinical courses were poor. Notably, all tumor tissues harbored TP53 mutation and PDGFRA amplification, while no tumor tissues harbored TERT promoter mutation, EGFR amplification and 7+/10-.
NCOG-17. THE CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATION BETWEEN EXECUTIVE FUNCTIONING AND MULTILAYER CENTRALITY OF THE FRONTOPARIETAL NETWORK IN GLIOMA PATIENTS
Authors: Marike van Lingen, Lucas Breedt, Jeroen Geurts, Arjan Hillebrand, Mathilde Kouwenhoven, Shanna Kulik, Jaap Reijneveld, Cornelis Stam, Philip Witt De Hamer, Mona Zimmermann, Fernando Santos, Linda Douw
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Many patients with glioma suffer from poorly understood executive functioning deficits before and/or after tumor resection. In the past decade, it has become increasingly clear that there is a complex interplay between glioma and both local and global functional activity and connectivity. Moreover, multilayer network integration of the frontoparietal network across multiple modalities has recently been found to explain individual differences in executive functioning in healthy subjects. OBJECTIVE To test whether multilayer frontoparietal network integration relates to individual differences in executive functioning before and after glioma resection. METHODS Patients with glioma (n = 37) underwent neuropsychological tests assessing word fluency, inhibition, and set shifting as components of executive functioning, and resting-state magnetoencephalography at T1 (at diagnosis, before resection) and T2 (1 year after resection). We constructed binary multilayer networks comprising six layers, with each layer representing frequency-specific functional connectivity between source-localized time series of 78 cortical regions. Average frontoparietal network multilayer eigenvector centrality, a measure for network integration, was calculated at both time points. Regression analyses were used to investigate associations with executive functioning. RESULTS At T1, lower multilayer integration (p = .017) and having epilepsy (p = .006) associated with poorer set shifting. Decreasing multilayer integration (p = .022) between T1 and T2 and not undergoing chemotherapy at T2 (p = .004) related to deteriorating set shifting. No significant associations were found for word fluency or inhibition. CONCLUSION As hypothesized, our results establish multilayer integration of the frontoparietal network as a cross-sectional and longitudinal correlate of executive functioning in glioma patients, further building upon the idea that glioma impacts the whole brain network and general cognitive functioning. However, multilayer integration did not significantly predict postoperative changes in executive functioning, limiting the direct clinical relevance of this measure.
NCMP-02. RENAL CELL CARCINOMA WITH METASTASIS TO THE CHOROID PLEXUS
Authors: Emily Kim, Danial Nadeem, James Nguyen, Hussam Ammar
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Intraventricular brain tumors make up only 0.9–4.5% of all cases of metastatic brain cancer.1 Involvement of the choroid plexus (CP) is even rarer with only a handful of documented cases. 2,3 Here we describe a case of bilateral multifocal metastasis to the choroid plexus appearing 10 years after nephrectomy in a male with stage IV renal cell carcinoma (RCC). CASE PRESENTATION: Our patient is a 74-year-old male with stage IV RCC diagnosed in 2006 and treated with radical nephrectomy and immunotherapy in 2011. In 2020, he presented to the emergency department with altered mental status. Brain magnetic resonance imaging (MRI) revealed an enhancing hemorrhagic lesion in the trigone of the right lateral ventricle (LV) and nodular thickening in the center of the right LV and trigone of the left LV, suggestive of metastatic disease. In 2021, the patient developed refractory seizures, and serial MRIs showed disease progression. He underwent several craniotomies with pathology confirming metastatic clear cell carcinoma, consistent with a renal primary. In 2022, the patient again presented with altered mental status. MRI revealed new avidly enhancing subcentimeter solid nodules in the CP of both LVs consistent with metastatic disease. Per the wishes of the family, palliative measures were pursued, and the patient was discharged home. CONCLUSION RCC can reappear several years after nephrectomy. 4 Metastatic RCC appears to have a unique propensity to spread to the ventricular system and the CP, which indicates late progression of disease. 1,5,6 While surgery may be viable if tumor burden is low, therapeutic options are limited in the advanced disease stages, as in our patient. Palliative care should be offered early to maximize remaining quality of life.
BIOM-50. THE IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF CIRCULAR RNA CIRC_63706 IN SONIC HEDGEHOG MEDULLOBLASTOMAS
Authors: Rudramani Pokhrel, Keisuke Katsushima, Stacie Stapleton, George Jallo, Eric Raabe, Charles Eberhart, Ranjan Perera
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is a central nervous system tumor that develops through various genetic, epigenetic, and non-coding (nc) RNA-related mechanisms, but the roles played by ncRNAs, particularly circular RNAs (circRNAs), remain poorly defined. CircRNAs are increasingly recognized as stable noncoding RNA therapeutic targets in many cancers, but little is known about their function, subtype specificity, and therapeutic potential in medulloblastomas. To determine medulloblastoma subgroup-specific circRNAs, we subjected RNA-seq data from 175 clinical medulloblastoma samples in four subgroups (SSH, WNT, G3, and G4) to a statistical and machine learning (random forest) pipeline and identified a group of medulloblastoma specific circular RNAs. CircRNA, circ_63706 was identified as sonic hedgehog (SHH) group specific and confirmed its expression by RNA-FISH analysis in clinical tissue samples (tissue microarrays). To identify the molecular function of circ_63706, we depleted circ_63706 in DAOY and ONS76 cells and subjected them to global RNA sequencing and lipid profiling. Circ_63706 resides in the coding gene Pericentrin (PCNT), which is known to be involved in congenital disorders. When Circ_63706 gets depleted by shRNA, it shows a significant decrease in cell proliferation and invasion in SSH cells, and mice implanted with circ_63706-deleted cells showed reduced tumor growth and extended survival compared to parental cells implant. At the molecular level, we identified circ_63706-deleted cells elevated total ceramide and oxidized lipids and reduced total triglyceride (TG). Our study implicates an identification of a novel oncogenic circular RNA in the medulloblastoma subgroup SSH and establishes its potential as a future therapeutic target.
NIMG-30. AI-BASED MOLECULAR CLASSIFICATION OF DIFFUSE GLIOMAS USING RAPID, LABEL-FREE OPTICAL HISTOLOGY
Authors: Todd Hollon, Cheng Jiang, Mustafa Nasir-Moin, Akhil Kondepudi, Asadur Chowdury, Wajd Al-Holou, Maria Castro, Pedro Lowenstein, Lisa Irina Wadiura, Georg Widhalm, Volker Neuschmelting, Reinecke David, Niklas von Spreckelsen, Mitchel S Berger, John Golfinos, Shawn L Hervey-Jumper, Sandra Camelo-Piragua, Honglak Lee, Christian Freudiger, Daniel Orringer
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. OBJECTIVE We aim to develop a rapid (&amp;lt; 90 seconds), AI-based diagnostic screening system that can provide molecular classification of diffuse gliomas and report its use in a prospective, multicenter, international clinical trial of diffuse glioma patients (n = 153). METHODS By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data in order to achieve optimal molecular classification performance. RESULTS One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for prospective patient enrollment and model testing. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy, respectively) as a first-line molecular diagnostic screening method for diffuse gliomas, detecting canonical and non-canonical IDH mutations with high accuracy. CONCLUSION Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery.
CSIG-36. NOTCH3 DRIVES MENINGIOMA TUMORIGENESIS AND RESISTANCE TO RADIOTHERAPY
Authors: Martha Cady, Abrar Choudhury, Calixto-Hope Lucas, Joanna J Phillips, Brisa Palikuqi, Nancy Ann Oberheim Bush, Ophir Klein, Shawn L Hervey-Jumper, Peter Dickinson, Stephen Magill, Aparna Bhaduri, Elizabeth Crouch, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract There are no approved targeted therapies for meningiomas and the cell types underlying meningeal tumorigenesis are incompletely understood. To address these limitations, we performed single-cell RNA sequencing of 57,114 cells from 8 human meningiomas and 54,607 cells from 3 canine meningiomas. Pseudotime, gene ontology, and copy number variant analyses revealed a population of pericyte-like meningioma cells that were conserved across human and canine tumors and were enriched in expression of Notch3 and other cancer stem cell genes. Deconvolution of cell types from bulk RNA sequencing and DNA methylation profiling of 200 human meningiomas integrated with immunohistochemistry (IHC), immunofluorescence (IF), and RNAScope demonstrated Notch3+ pericytes and Notch3 expression were enriched in high grade or Immune-enriched meningiomas, which were distinguished from other meningioma DNA methylation groups by genes driving vasculature development. IHC and IF of human meninges integrated with lineage tracing approaches using Notch3-CreERT2 ROSAmT/mG alleles in mice demonstrated Notch3 expression was restricted to the perivascular stem cell niche during meningeal development and homeostasis. Mice harboring Notch3-CreERT2 Nf2fl/fl alleles developed meningeal hyperproliferation. Overexpression of constitutively activated Notch3 (Notch3AICD) in Immune-enriched human meningioma cells increased the expression of cancer stem cell genes, driving clonogenic growth in vitro, limiting dilution tumor-initiating capacity in vivo, and resistance to radiotherapy in vivo. A selective Notch3 neutralizing antibody (αNRR3) blocked meningioma cell proliferation and expression of Notch3 target genes, inhibiting meningioma xenograft growth and prolonging overall survival. Single-cell RNA sequencing of 187,366 cells from meningioma xenografts after αNRR3 or radiotherapy treatment ± Notch3AICD overexpression revealed distinct meningioma cell-intrinsic or cell-extrinsic mechanisms driving responses to radiotherapy or αNRR3, respectively. Combined treatment with αNRR3 and radiotherapy additively blocked meningioma xenograft growth and extended survival benefit. In sum, these data shed light on a novel cell type, molecular mechanism, and therapeutic vulnerability in the most common primary intracranial tumor.